Microfilament-coordinated adhesion dynamics drives single cell migration and shapes whole tissues [version 1; Referees:4:approved]

Cell adhesion to the substratum and/or other cells is a crucial step of cell migration. While essential in the case of solitary migrating cells (for example, immune cells), it becomes particularly important in collective cell migration, in which cells maintain contact with their neighbors while moving directionally. Adhesive coordination is paramount in physiological contexts (for example, during organogenesis) but also in pathology (for example, tumor metastasis). In this review, we address the need for a coordinated regulation of cell-cell and cell-matrix adhesions during collective cell migration. We emphasize the role of the actin cytoskeleton as an intracellular integrator of cadherin- and integrin-based adhesions and the emerging role of mechanics in the maintenance, reinforcement, and turnover of adhesive contacts. Recent advances in understanding the mechanical regulation of several components of cadherin and integrin adhesions allow us to revisit the adhesive clutch hypothesis that controls the degree of adhesive engagement during protrusion. Finally, we provide a brief overview of the major impact of these discoveries when using more physiological three-dimensional models of single and collective cell migration

Characterization of mutant versions of the R-RAS2/TC21 GTPase found in tumors

The R-RAS2 GTP hydrolase (GTPase) (also known as TC21) has been traditionally considered quite similar to classical RAS proteins at the regulatory and signaling levels. Recently, a long-tail hotspot mutation targeting the R-RAS2/TC21 Gln72 residue (Q72L) was identified as a potent oncogenic driver. Additional point mutations were also found in other tumors at low frequencies. Despite this, little information is available regarding the transforming role of these mutant versions and their relevance for the tumorigenic properties of already-transformed cancer cells. Here, we report that many of the RRAS2 mutations found in human cancers are highly transforming when expressed in immortalized cell lines. Moreover, the expression of endogenous R-RAS2Q72L is important for maintaining optimal levels of PI3K and ERK activities as well as for the adhesion, invasiveness, proliferation, and mitochondrial respiration of ovarian and breast cancer cell lines. Endogenous R-RAS2Q72L also regulates gene expression programs linked to both cell adhesion and inflammatory/immune-related responses. Endogenous R-RAS2Q72L is also quite relevant for the in vivo tumorigenic activity of these cells. This dependency is observed even though these cancer cell lines bear concurrent gain-of-function mutations in genes encoding RAS signaling elements. Finally, we show that endogenous R-RAS2, unlike the case of classical RAS proteins, specifically localizes in focal adhesions. Collectively, these results indicate that gain-of-function mutations of R-RAS2/TC21 play roles in tumor initiation and maintenance that are not fully redundant with those regulated by classical RAS oncoproteins

Genetic and environmental factors related to the development of myopic maculopathy in Spanish patients

High myopia and the subsequent degenerative changes of the retina, choroid, and sclera, known as myopic maculopathy (MM), are a serious visual problem in many Asian countries, and are beginning to be so in the south of Europe, especially in the Mediterranean. It is therefore necessary to carry out genetic and environmental studies to determine the possible causes of this disease. This study aims to verify if the genetic factors that have been most related to Asian populations are also associated in two Spanish cohorts. Eight SNPs from six genes (PAX6,SCO2,CCDC102B,BLID,chromosome 15q14, andCOL8A1) along with demographic, ophthalmic and environmental factors were analysed in two cohorts from a total of 365 highly myopic subjects and 177 control subjects. The genetic analysis showed thatCOL8A1SNP rs13095226 was associated with the development of choroidal neovascularization (CNV) and also seems to play an important role in the increase of axial length. The SNP rs634990 ofchromosome 15q14also showed a significant association with MM, although this was lost after the Bonferroni correction. Additional demographic and environmental factors, namely age, sex, smoking status, and pregnancy history, were also found to be associated with MM and CNV in this population

Cranial and extracranial giant cell arteritis do not exhibit differences in the IL6 -174 G/C gene polymorphism

Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA

The presence of both HLA-DRB1[*]04:01 and HLA-B[*]15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

Objectives: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. Methods: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. Results: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. Conclusions: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from ‘‘Instituto de Salud Carlos III’’ (ISCIII) (Spain). However, this research did not receive any specific grant from funding agencies in the commercial or not-for-profit sectors

Outcomes and prognostic factors of adults with refractory or relapsed T-cell acute lymphoblastic leukemia included in measurable residual disease-oriented trials

Despite high complete remission (CR) rates with frontline therapy, relapses are frequent in adults with T-cell acute lymphoblastic leukemia (T-ALL) with limited salvage options. We analyzed the outcomes and prognostic factors for CR to salvage therapy and overall survival (OS) of patients with R/R T-ALL included in two prospective measurable residual disease-oriented trials. Seventy-five patients (70 relapsed, 5 refractory) were identified. Relapses occurred in bone marrow, isolated or combined in 50 patients, and in the central nervous system (CNS; isolated or combined) in 20. Second CR was attained in 30/75 patients (40%). Treatment with FLAG-Ida and isolated CNS relapse were independently associated with a higher CR rate after first salvage therapy. The median OS was 6.2 (95% confidence interval [CI], 3.9–8.6) months, with a 4-year OS probability of 18% (95% CI, 9%–27%). No differences in survival were observed according to the treatment with hematopoietic stem cell transplantation in patients in CR after first salvage therapy. Multivariable analysis showed a ≥12-month interval between first CR and relapse, CR after first salvage therapy and isolated CNS relapse as favorable prognostic factors for OS with hazard ratios (HR) (95% CI) of 1.931 (1.109–3.362), 2.958 (1.640–5.334), and 2.976 (1.157–7.655), respectively. This study confirms the poor outcomes of adults with R/R T-ALL among whom FLAG-Ida was the best of the rescue therapies evaluated. Late relapse, CR after first rescue therapy and isolated CNS relapse showed prognostic impact on survival. More effective rescue therapies are needed in adults with R/R T-ALL.La Caixa" Foundation and ISCIII, Grant/ Award Number: PI19/01828; Generalitat de Catalunya (GRC), Grant/Award Number: 2017 SGR28

Healthcare workers hospitalized due to COVID-19 have no higher risk of death than general population. Data from the Spanish SEMI-COVID-19 Registry

Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20-65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067-0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality

Docencia en Derecho y Proceso: hacia un aprendizaje de calidad en la Universidad

Presentación / Esther Pillado González (pp. 11-13). -- La adaptación de la asignatura derecho procesal penal al grado en la Universidad Carlos III de Madrid: un proceso aún inconcluso / Juan Manuel Alcoceba Gil (pp. 17-26). -- Role playing, cooperación competitiva y method case en la docencia-aprendizaje del Derecho Procesal / Cristina Alonso Salgado (pp. 27-35). -- Esquemas y materiales básicos para explicar en el grado en derecho el sistema de impugnación de actos jurídicos de las administraciones públicas en España / Roberto O. Bustillo Bolado (pp. 37-40). -- Nuevas herramientas y técnicas para la docencia del derecho / Juan Cámara Ruiz (pp. 41-51). -- Novas técnicas na docência em direito / Marco Carvalho Gonçalves (pp. 53-60). -- Experiência de lecionação em Direito em cursos não jurídicos – a lecionação da UC de Direito das Crianças e Jovens ao Mestrado em Intervenção Psicossocial com Crianças, Jovens e Famílias do Instituto de Educação / Cristina M. A. Dias (pp. 61-67). -- Los programas universitarios para mayores: la docencia en Derecho en la Universidad de Vigo / Teresa Estévez Abeleira (pp. 69-79). -- El aprendizaje activo del Derecho Procesal / María Dolores Fernández Fustes (81-92). -- El aprendizaje como método de adquirir los conocimientos / Raquel López Jiménez (pp. 93-101). -- Alumnado con necesidades especiales en el grado en derecho: el reto de la normalización e inclusión / Ángel M. Mariño de Andrés y M. Teresa Martínez Táboas (pp. 103-110). -- Docencia y proceso penal: intentando experimentar el proceso / Sabela Oubiña Barbolla (pp. 111-127). -- La integración de las redes sociales en la enseñanza del Derecho Penal / Natalia Pérez Rivas (pp. 129-135). -- Análisis y prospectiva de una plataforma e-learning en ciencias jurídicas / Amparo Rodríguez Damián, Margarita Pino Juste, Arturo Casar Sarasola y Manuel Pérez Cota (pp. 137-149). -- La evaluación de competencias en las materias “prácticas externas” del Máster Universitario en Abogacía: problemas y retos / Mónica Siota Álvarez (pp. 151-164). -- La enseñanza del derecho procesal a través del método del caso / Helena Soleto Muñoz (pp. 165-178). -- A aprendizagem activa do Direito Processual – reflexão sobre velhos hábitos e novas práticas / Lurdes Varregoso Mesquita (pp. 179-189). -- Acão executiva e metodologia aplicada – demonstração de caso / Lurdes Varregoso Mesquita, Diana Leiras (pp. 191-201). -- Derecho Constitucional y género / Almudena Bergareche Gros (pp. 205-216). -- Aproximación al fenómeno de la violencia de género a través de las novelas como recurso didáctico / María Castro Corredoira (pp. 217-227). -- La formación en género en derecho penal: el cine como recurso didáctico / Natalia Pérez Rivas, Fernando Vázquez-Portomeñe Seijas (pp. 229-240). -- Cuestiones controvertidas de la docencia en el ámbito del derecho constitucional: la perspectiva de género y el principio de transversalidad / Pablo Riquelme Vázquez (pp. 241-253). -- Storytelling y cine extranjero en la explicación del sistema de justicia penal español / Cristina Alonso Salgado (pp. 257-263). -- Direito e Cinema. Breve reflexão a partir da experiência da docência ao 1.º ano do curso de Direito / Maria Clara Calheiros (pp. 265-273). -- El cine como opción pedagógica en la enseñanza del derecho penal / Fernando Vázquez-Portomeñe Seijas y María Castro Corredoira (pp. 275-286). -- El jurista del siglo XXI y la Universidad del siglo pasado: ¿realidades irreconciliables? / Amaya Arnáiz Serrano (pp. 289-307). -- La formación del abogado del siglo XXI / Emiliano Carretero Morales (pp. 309-321). -- El cambio del perfil del alumno y su influencia a la enseñanza superior / Anna Fiodorova (pp. 323-335). -- La enseñanza del derecho en el marco Bolonia: reflexiones en base a las distintas tradiciones jurídicas / Mercedes Llorente Sánchez-Arjona (pp. 337-355)

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements